Use of recombinant fibrinogen-like domain of angiopoietin-like 4 for treating adverse post-ischemic cardiac remodeling in a patient who experienced a myocardial infarction

Abstract

Ischemic heart diseases are leading causes of death and reduced life quality worldwide. Although revascularization strategies significantly reduce mortality after acute myocardial infarction (MI), a large number of patients with MI develop chronic heart failure over time. The inventors previously reported that human recombinant ANGPTL4 counteracts ischemia-induced vascular endothelial growth factor signaling and disruption of endothelial cell junctions thus inhibiting vascular permeability. When administered before MI, the inventors could show that ANGPTL4 leads to protection of the coronary capillary network, reduction of no-reflow and infarct size in mice. The inventors also showed that the therapeutic effects observed with ANGPTL4 in ischemic conditions are not due to the CCD fragments but are brought by the FLD fragment (WO2016/110498). To further test the therapeutic potential of the FLD of ANGPTL4 at the onset of reperfusion, the inventors here used a pig model in a clinically relevant model of acute myocardial infarction which can be easily and safely translated to patient treatment. The inventors demonstrated that local (antegrade) delivery of FLD ANGPTL4 to the infarcted pig heart can target the affected regions in an efficient and clinically relevant manner. A single dose of FLD of ANGPTL4 improved heart function, infarct size, fibrosis, and adverse remodeling parameters 28 days after MI. Short term MI experiments along with complementary murine studies revealed myocardial protection. Thus, a single dose of FLD of ANGPTL4 is capable of reducing ischemia-reperfusion injury and protects against deleterious post-ischemic cardiac remodeling and consecutive ischemic heart failure.

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